This study (https://pdrisk.ninds.nih.gov) will determine if people who have risk factors for Parkinson disease (PD) have biomarkers (objective ways to measure a disease process) that show that the disease process is actually going on, and if people who have abnormal biomarkers go on to develop PD during several years of follow-up. Biomarkers of Parkinson disease (PD) might identify people who are healthy now but may develop the disease later in life.

Healthy volunteers and people who have certain risk factors for developing PD who are between 18 and 70 years of age may be eligible for this study. People with the following risk factors are included:

Measurement of blood pressure and pulse rate while lying down and then standing up

Blood draw for genetic testing

Inpatient testing at the NIH Clinical Center for 2-3 days, including:

Measurements while blowing against a resistance

Measurements of blood pressure and pulse rate

Blood draws for levels of various chemicals

PET and MRI scanning

Lumbar puncture (spinal tap)

Electrocardiogram

Skin electrical conduction test (test of sweat production)

Skin and core temperature measurements

Transcranial ultrasound (sound-wave test of the head)

Follow-up testing (up to five visits in 18-month intervals) to repeat some of the tests listed above, excluding the genetic testing and spinal tap

Detailed Description

Objective: This Protocol is to test whether individuals with putative risk factors for Parkinson disease (PD) have abnormal values for biomarkers of central or peripheral catecholaminergic innervation and whether at-risk individuals with positive biomarkers develop PD within up to 7.5 years of follow-up.

Study Population: The subjects are individuals who may be at risk for developing PD, because of (a) genetic risk i.e., a family history of PD or genotypic abnormalities known to be associated statistically with PD; (b) olfactory dysfunction i.e., decreased ability to distinguish among odors; (c) symptomatic rapid eye movement (REM) sleep behavior disorder (RBD); or (d) orthostatic hypotension. A total of 200 at-risk subjects undergo catecholaminergic biomarker testing by 6-[18F]fluorodopa brain and 6-[18F]fluorodopamine cardiac scanning. At-risk subjects with positive biomarkers are compared to at-risk subjects without positive biomarkers, in terms of development of PD during follow-up. Up to 20 control subjects are included, to add to a database of normal values for catecholaminergic biomarkers.

Design: The study includes four phases recruitment, screening, laboratory biomarkers testing, and follow-up. Recruitment is by advertisement and a web site questionnaire of self-reported risk. A screening examination is done at the NIH Clinical Center, to confirm risk status. Based on the screening examination results, subjects undergo clinical laboratory testing, to identify central and peripheral catecholaminergic denervation. In the follow-up phase, subjects are re-tested approximately every 18 months for a total of up to 5 re-evaluations (90 months, or 7.5 years), to detect onset of the characteristic movement disorder in PD and follow the status of catecholaminergic innervation.

Outcome Measures:

Primary: Diagnosis of PD by a board certified neurologist who is blinded to risk factor status and the results of catecholaminergic biomarkers testing. If PD diagnosed, time to diagnosis.

* Includes publications given by the data provider as well as publications
identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.

Recruitment Information

Recruitment Status ICMJE

Recruiting

Estimated Enrollment ICMJE

220

Completion Date

Not Provided

Primary Completion Date

Not Provided

Eligibility Criteria ICMJE

INCLUSION CRITERIA:

Individuals with one or more of the following characteristics will be considered to be at risk and eligible for entering the Screening Examination phase. Priority will go to those with multiple risk factors. Subjects with at least 3 of the 4 risk factors will be invited to the Screening Examination. Control subjects will have none of these characteristics:

Genetic risk is assessed at the time of the Screening Examination in two ways by creation of a pedigree and by genotyping. The pedigree shows diagrammatically the family history with respect to Parkinson disease. Genotyping is by DNA extraction and analysis for mutations of the LRRK2 or the alpha-synuclein gene or for alpha-synuclein gene replication. Either a positive family history (one or more immediate family members with PD) or positive DNA test results (LRRK2 or alpha-synuclein) satisfy the risk factor criterion for genetic risk. Other DNA analyses may be done subsequently; however, those results will not be considered relevant to genetic risk at the time of entry.

Olfactory Dysfunction is identified by the UPSIT. Decreased olfactory function, as indicated by less than a normal score, satisfies this risk factor criterion. In the event of a medical history indicating a secondary cause of decreased olfaction, decreased olfactory function as measured by the UPSIT is not be taken as satisfying this risk factor criterion.

REM Behavior Disorder (RBD) is identified by a history of sleep-related, injurious, potentially injurious, or disruptive behaviors (i.e., dream enactment behavior). Although polysomnographic evidence of REM sleep without atonia is a supportive clinical laboratory finding, the occurrence of these sleep-related abnormal behaviors is considered necessary and sufficient to satisfy the risk factor criterion. To satisfy the risk factor criterion, the individual must have movements of the body or limbs associated with dreaming and at least one of the following: potentially harmful sleep behavior, dreams that appear to be acted out, and sleep behavior that disrupts sleep continuity.

Orthostatic Hypotension is assessed by measurement of the blood pressure after the subject has been supine at rest for at least 15 minutes and then after the subject has stood upright for 5 minutes. A fall in systolic pressure of 20 mm Hg or more and a fall in diastolic pressure of 10 mm Hg or more at the time of the Screening Examination satisfy this risk factor criterion.

EXCLUSION CRITERIA:

Age< TAB> - People younger than 18 years old or older than 70 years old are excluded.

Risk - A candidate subject is excluded if, in the judgment of the Principal Investigator, Protocol participation would place the subject at substantially increased acute medical risk. This includes the risks associated with air travel to the NIH. A candidate subject may be excluded from the study if, in the opinion of the Principal Investigator or Clinical Director, the medical risk outweighs the potential scientific benefit. An example of such risk is inability to travel safely to the NIH Clinical Center, in Bethesda, Maryland, due to a neurological disorder associated with frequent falls.

Disqualifying Conditions - A candidate subject is excluded if there is a disqualifying condition. Examples of disqualifying conditions are insulin-dependent diabetes, hepatic or renal failure, symptomatic congestive heart failure, severe anemia, psychosis, ventricular arrhythmias, and symptomatic coronary heart disease. Persons with dementia interfering with their ability to provide informed consent are excluded. If dementia is suspected, such as by score on the mini-mental status examination of < 24, then a bioethics consult will be obtained. If a subject develops dementia during the study, with a mini-mental score < 24, the subject is excluded from further participation in the study. Persons who are unable to undergo MRI safely, due to implanted metal, are excluded from the MRI procedure. A candidate participant will be excluded if the person is unable to travel safely to the NIH Clinical Center, in Bethesda, Maryland, such as due to a neurological disorder associated with frequent falls.

Medications - A candidate subject is excluded if clinical considerations require continued treatment with a drug likely to interfere with the scientific results. Chronic, ongoing use of drugs such as tricyclic antidepressants that affect the clinical laboratory results exclude candidate subjects. People with known or suspected allergy or hypersensitivity to any test drug are excluded. Candidate subjects are not to discontinue any medications before discussion with the Principal Investigator, Research Nurse, Nurse Practitioner, or Clinical Fellow. A candidate participant will be excluded if the person is taking a medication that cannot safely be discontinued or replaced temporarily. An example of such a medication is a tricyclic anti-depressant. If it is decided that discontinuing anticoagulant medications would be unsafe, then the subject will be excluded from the lumbar puncture procedure.

Herbal Medicines and Dietary Supplements - If a subject wishes to continue herbal medicines or dietary supplements while on study, and search of the available medical literature fails to identify effects that are known or expected to interfere with the experimental results, then the subject may participate, at the discretion of Principal Investigator.

Practical Limitations - People in whom we feel it would be difficult to insert a catheter into a vein may be excluded. People who are not expected clinically to tolerate lying still supine during the testing will be excluded. If it is medically contraindicated to have an MRI or a lumbar puncture subjects will be excluded from those procedures.

Pregnancy - Pregnant or lactating women are excluded. Women of childbearing potential must have a negative urine or blood test for pregnancy done within 24 hours before any testing involving radioactivity.